NATURAL KILLER (NK) CELLS MAY RECOGNIZE HLA CLASS I-PEPTIDE COMBINATIONS NK cells are lymphocytes that do not rearrange or express immunoglobulin or T cell receptor genes. NK cells kill virally infected cells, tumor cells, and allogeneic cells with broad specificity. The mechanisms of target cell recognition by NK cells are currently not entirely understood. At least two mechanisms of killing by NK cells exist. One mechanism is called "antibody- dependent cytotoxicity", which involves an NK membrane receptor CD16 binding the Fc portion of an antibody specific for a target cell antigen. The second mechanism of killing is not via the CD16. This killing is affected by the expression of the major histocompatibility complex class I molecules (in humans called HLA class I), normally present on nearly all cells. In HLA class I molecules alpha 1 and alpha 2 domain alpha helices are supported by a beta-pleated sheet, forming the peptide binding groove. HLA bound peptides are derived from proteins synthesized inside the same cell. HLA peptide binding groove residues determine which peptides are bound. HLA-peptide complexes are sampled by the T cells via the T cell receptor. We are studying the ability of NK cells to recognize peptide-HLA class I combinations by measuring the killing activity in 51Cr-release assays. NK cells from peripheral blood of 7 healthy human donors are mixed with 51Cr- labeled target cells. The target cells are self-HLA class I negative human lymphoblastoid cells, 721.221, transfected with HLA- B7 common type, or with one of HLA-B7 single point mutants. The levels of HLA-B7 expression are determined by specific HLA class I and HLA-B7 monoclonal antibodies, labeled and analysed by fluorescence activated cell sorter. 27 mutants have so far been tested. Of 11 mutants that significantly increased target cell susceptibility to killing by NK cells in comparison with the common type HLA-B7, 7 are in the position to interact with the bound peptide. These data imply that NK cells recognize specific HLA- peptide complexes, and that NK cells may express a molecule similar to the T cell receptor. Key words: natural killer cells, cytotoxicity, HLA class I, HLA- B7.